We aimed to assess the incidence, clinical and biochemical course of immunotherapy-induced thyroiditis and its implication on patients' survival, based on an extensive clinical experience from a ...tertiary cancer center.
Analyses were based on data from the electronic medical records of cancer patients treated with CPIs. Data included demographic characteristics, cancer type, Thyroid function tests (TFT), and survival.
Thyroid function tests were available for 934 patients. After excluding patients with impaired baseline TFT or levothyroxine treatment, 754 euthyroid patients were included in the core analyses. Of those, 301 (39.9%) patients developed thyroid dysfunction ('thyroiditis'). Thyroiditis was more prevalent in patients with renal cell carcinoma than other types of cancer. Survival rates were comparable in patients who developed thyroiditis and in those who did not. during the 5 years follow-up period, there was a non-significant trend toward improved survival in patients who developed TD in four predefined groups: melanoma, lung cancer, renal cell carcinoma, and transitional cell carcinoma. Nevertheless, we observed a highly significant survival benefit for patients with renal cell carcinoma who developed TD (HR = 0.19, 95% CI 0.06-0.60; p = 0.005).
Thyroiditis is common, often asymptomatic, and is more prevalent in patients treated with combinations of nivolumab and PD-L1 inhibitors, and in patients with renal cell carcinoma. Thyroiditis was associated with a trend for a survival benefit, particularly in patients with renal cell carcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Approximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts.
This is a multicenter, retrospective ...study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected.
A total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases–evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation.
Osimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind.
Targeting angiogenesis in lung cancer Daher, Sameh; Bar, Jair
Memo - Magazine of European medical oncology,
03/2018, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Summary
Angiogenesis inhibition is a promising way to inhibit and eradicate cancer. Many attempts have been made to use this tool for the treatment of lung cancer. Some success has been reported, and ...antiangiogenic drugs are actively being investigated in combination with other types of anticancer treatments.
2557
Background: Despite the remarkable success of immunotherapy, only ~20-40% of cancer patients display an extended durable response. Pre-existing biomarkers for immunotherapy outcome are ...significantly limited in their predictive power, e.g., PDL-1 expression by tumor cells (AUC ~ 0.6-0.75). This requires additional efforts to search for new approaches to discover new biomarkers in immune-oncology. While mice are the most widely used and cost-effective model to study human disease, translating preclinical biomarkers into clinical practice faces significant obstacles – in part due to the lack of diverse or appropriate models. In this study we have taken a holistic approach to search for new biomarkers for immunotherapy outcomes, with the aim to improve translatability of the findings and their validity in cancer patients. Methods: Several pre-clinical models were used, each capturing one possible mechanistic aspect of immunotherapy response, such as tumor- and host-dependency, in order to reflect the variability seen in human cancers. These models have been analyzed for myeloid cell composition within tumors and peripheral blood using high throughput techniques such as single-cell RNA sequencing and mass cytometry, followed by rigorous bioinformatic tools. Peripheral blood mononuclear cells (PBMCs) were obtained from non-small cell lung cancer (NSCLC, n = 34) and melanoma (n = 38) patients prior to immune-checkpoint inhibitor backbone therapy as monotherapy or in combination with chemotherapy. These results were validated on additional human bulk mRNA datasets (n = 417). Results: Using the preclinical models, we identified interferon-stimulated, Ly6E
hi
neutrophils as a pre-treatment, blood-borne biomarker for anti-PD1 response. These results were validated in PBMCs of advanced metastatic NSCLC and malignant melanoma patients predominately treated with immune checkpoint inhibitor-based therapy, with a high degree of accuracy (AUC ~ 0.9). These results were also validated in independent cohorts of immunotherapy-treated patients with other cancer types obtained from bulk mRNA datasets including renal cell carcinoma (n = 109), urothelial carcinoma (n = 228) and additional melanoma patients (n = 80). Functional studies revealed that Ly6E
hi
neutrophils sensitize otherwise resistant tumors to anti-PD1 therapy, in part by directly activating cytotoxic T cells and contributing to tumor cell killing, while operate upstream of T cells in the immunotherapy response. Conclusions: Our study demonstrates a pragmatic approach to search for new, clinically relevant and functionally active cellular biomarkers for immunotherapy outcomes in humans. This study paves the way for a conceptual framework to advance the field of immuno-oncology by utilizing this approach for successful clinical trials.
Squamous non-small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor ...veliparib in combination with conventional chemotherapy for advanced sqNSCLC (NCT02106546).
Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52).
Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio HR, 0.905; 95% CI, 0.744 to 1.101;
= .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0
9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0
14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm.
In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.
Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients—emphasizing the importance of predictive biomarkers in clinical decision-making ...and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6Ehi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6Ehi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6Ehi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans.
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•Ly6Ehi neutrophils are interferon-stimulated cells present in both mouse and human•Ly6Ehi neutrophils accurately predict immunotherapy outcomes in different cancer types•Activation of the STING pathway in tumors accounts for Ly6Ehi neutrophil enrichment•Ly6Ehi neutrophils sensitize otherwise resistant tumors to immunotherapy in mice
A lack of reliable, highly predictive biomarkers remains a major obstacle in immuno-oncology. In this study, Benguigui et al. discover a promising new biomarker: interferon-stimulated, Ly6Ehi neutrophils—whose frequency in the blood of both mice and patients strongly correlates with immunotherapy outcomes across cancer types.
8642 Background: Osimertinib is broadly used for advanced EGFR-mutant NSCLC patients. However, the activity of osimertinib is not fully characterized in tumors harboring uncommon EGFR mutations, ...which represents about 10% of EGFR-mutated NSCLC cases. Hence, we conducted a systematic review and meta-analysis to assess the efficacy and safety of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations. Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. Uncommon EGFR mutations were defined as any mutation other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with I 2 statistics and random-effect model was used for a meta-analysis. Results: Nine studies comprising 331 patients were included. Median follow-up ranged from 12.6 to 22.0 months (mos). Median age in each study ranged from 51 to 72 years old (table). Overall, 62% (205/331) of patients were female and 77% (256/331) of patients had an ECOG PS ≤1. About 78% (258/331) of patients received Osimertinib in a 1 st line setting. Uncommon tumoral EGFR mutations included G719X in 40% (131/331) of patients, L861X in 27% (91/331), and S768I in 15% (49/331). Pooled analysis showed an overall ORR of 49.5% (95% CI, 42.2 – 56.9), a DCR of 90.2% (95% CI, 86.2 – 94.3), a median OS of 24.5 mos (95% CI, 11.9 – 24.5), a median PFS of 9.5 mos (95% CI, 8.2 – 11.0), and a median DOR of 17.4 mos (95% CI, 7.9 – 22.7). Intracranial (i) efficacy had an iORR of 50.3% (95% CI, 30.3 – 70.3), an iDCR of 92.8% (95% CI, 76.2 – 100), and a median iPFS of 6.1 mos (95% CI, 4.5 – 6.6). In a subgroup analysis according to EGFR mutation, overall ORR was significantly different in patients with tumoral G719X, S768I and L861 mutations (ORRs of 28.8%, 33.3%, and 67.7%, respectively, p for subgroup differences < 0.01). Overall, osimertinib was well tolerated with a frequency of all-grade AEs of 86.2% (95% CI, 61.2 – 100) and ≥ G3 of 18.0% (95% CI, 1.2 – 34.7). Conclusions: This systematic review and meta-analysis suggests that patients with NSCLC with uncommon tumoral EGFR mutations may benefit from osimertinib treatment. Patients harboring tumoral L861 mutation achieved a significantly higher ORR compared to the modest ORR in G719X, S768I cases. Table: see text
8547 Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease ...is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo range: 1.2-2.9 vs 1.6 mo range: 1.2-2.9); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . Table: see text
Breast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and ...MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES).
Chemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers.
TNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors.
Our novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies.
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